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Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(9):1859-1866; doi:10.1093/carcin/bgm079
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Loss of p27Kip1 enhances tumor progression in chronic hepatocyte injury-induced liver tumorigenesis with widely ranging effects on Cdk2 or Cdc2 activation

Daqian Sun1,2,{dagger}, Hao Ren1,2,4,{dagger}, Michael Oertel2, Rani S. Sellers3 and Liang Zhu1,2,*

1 Department of Developmental and Molecular Biology
2 Department of Medicine
3 Department of Pathology, Marion Bessin Liver Research Center and Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
4 Present address: Hao Ren's present address is Department of Microbiology, Second Military Medical University, Shanghai 200433, China

* To whom correspondence should be addressed. Tel: 718-430-3320; Fax: 718-430-8975; Email: lizhu{at}aecom.yu.edu

Effects of p27Kip1 inactivation on tumorigenesis vary from promotion to prevention dependent on the mouse models used. When p27 inactivation has a positive effect on tumorigenesis, de-regulated activation of cyclin-dependent kinases (Cdks) is generally believed to be the underlying mechanism since the function of p27 as an inhibitor of Cdks is firmly established. Here, we determined the effects of p27 inactivation on disease progression and Cdk activation in mouse liver tumorigenesis that originates from hepatocyte regenerative proliferation in response to chronic liver injury, an established etiology in most human liver cancer. Our results show that inactivation of p27 did not affect early-stage hepatocyte regenerative proliferation but promoted tumor cell proliferation and progression in the late stage of the disease. Interestingly, Cdc2 over-expression was observed in all and cyclin E1 was over-expressed in half of the late-stage tumors regardless of p27 status; and p27 inactivation led to significant activation of Cdk2 or Cdc2 only in half of the p27-deficient tumors. These results reveal a tumor suppressor role of p27 in chronic hepatocyte injury-induced liver tumorigenesis and, at the same time, the need to further study the mechanisms for tumor promotion by p27 inactivation.

Abbreviations: Cdks, cyclin-dependent kinases; HBV, hepatitis B virus; PCNA, proliferating cell nuclear antigen

{dagger} Both authors contributed equally to this work.

Received November 28, 2006; revised March 30, 2007; accepted April 2, 2007.


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